Brand name: Mexitil
Drug class: Class Ib Antiarrhythmics
VA class: CV300
Chemical name: 1-(2,6-Dimethylphenoxy)-2-propanamine hydrochloride
Molecular formula: C₁₁H₁₇NO•HCl
CAS number: 5370-01-4

Medically reviewed by Drugs.com on Nov 6, 2023. Written by ASHP.

Introduction

Antiarrhythmic agent; a local anesthetic-type, class 1B agent.^{1 8 10 11 12 24 34}

Uses for Mexiletine

Ventricular Arrhythmias

Treatment of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia).^{1 20 34} Use for less severe arrhythmias is notrecommended.^{1 34 44}

Can reduce ventricular premature contractions (VPCs)^{† [off-label]}, paired VPCs^{† [off-label]}, and nonsustained ventricular tachycardia^{† [off-label]} and can suppress the recurrence of ventricular tachycardia and/or fibrillation in patients with ventricular tachycardia and/or fibrillation^{† [off-label]}.^{1 10 12 13 14 15 16 17 18 19 20 34} Avoid treatment of asymptomatic VPCs.^{1 34}

Has been effective in some patients for the treatment of ventricular arrhythmias unresponsive to other antiarrhythmic agents^{† [off-label]}.^{10 11 12 13 16 19 20}

Diabetic Neuropathy

Has been used with equivocal results in the management of painful diabetic neuropathy^†;^{26 27 28 29 30 31 32 39 45 46} pending further accumulation of data from well-designed studies, use only in patients who do not respond to or cannot tolerate more established therapies.^{32 39}

Related/similar drugs

amiodarone, lidocaine, verapamil, flecainide, propafenone, dofetilide, Pacerone

Mexiletine Dosage and Administration

General

Ventricular Arrhythmias

• Individualize dosage carefully according to individual response, tolerance, general condition, and cardiovascular status.^{1 12 17 34 44 46}

• Clinical and ECG evaluation (e.g., Holter monitoring) is recommended to determine whether the desired antiarrhythmic effect has been achieved and to guide dosage titration and adjustment.^{1 12 14 17 18 34 44}

• Initiate therapy in a hospital.^{1 34} Patients at high risk for developing life-threatening arrhythmias after discontinuance of existing antiarrhythmic therapy should be hospitalized.^{1 34}

Administration

Oral Administration

Administer orally, generally every 8 hours.^{1 10 12 15}

Administer with food or antacids to minimize adverse GI effects.^{1 10 11 12 34 44 46}

Dosage

Available as mexiletine hydrochloride; dosage expressed in terms of the salt.¹

Adults

Ventricular Arrhythmias

Oral

If rapid control of arrhythmia is essential, 400-mg loading dose followed by 200 mg in 8 hours.^{1 12 13 15 34} If rapid control of arrhythmia is not essential, initial dosage of 200 mg every 8 hours.^{1 17 20 34}

If necessary, adjust dosage at intervals of at least 2–3 days in increments or decrements of 50 or 100 mg.^{1 13 34} 200–300 mg every 8 hours usually results in satisfactory control of arrhythmias.^{1 10 17 34} If satisfactory control is not achieved and patient tolerates 300 mg every 8 hours, increase dosage to 400 mg every 8 hours.^{1 11 17 34}

If adequate control of arrhythmia has been achieved at doses ≤300 mg every 8 hours, total dosage may be administered twice daily (every 12 hours) with close monitoring of degree of ventricular ectopy suppression.^{1 34}

Switching from Another Class I Antiarrhythmic Agent

Oral

200 mg as a single dose, administered 6–12 hours after last dose of quinidine sulfate or disopyramide, 3–6 hours after last dose of procainamide, or 8–12 hours after last dose of tocainide.^{1 34} Adjust subsequent doses according to individual requirements.^{1 34}

When switching to mexiletine from IV lidocaine, discontinue lidocaine infusion at the time of administration of the first dose of mexiletine; however, keep infusion line open until arrhythmia appears to be satisfactorily suppressed.^{1 34} Closely monitor patient.^{1 34}

Diabetic Neuropathy†

Oral

Initial dosage of 200 mg once daily has been used;^{31 32 39 44 46} dosage increased at 2-day intervals to 200 mg twice daily and then 200 mg 3 times daily.^{32 39 46}

Prescribing Limits

Adults

Ventricular Arrhythmias

Oral

Maximum 400 mg every 8 hours^{1 11 17 34} (1.2 g daily).^{1 13 34 46}

If given twice daily, maximum 450 mg every 12 hours.^{1 34}

Diabetic Neuropathy†

Oral

Dosage generally should not exceed 1.2 g daily.^{32 39 46}

Special Populations

Hepatic Impairment

Consider dosage reduction in patients with hepatic impairment (including those with hepatic dysfunction secondary to CHF).^{1 8 12 34 44}

Renal Impairment

Dosage adjustment not required.^{1 8 12 21 34}

Cautions for Mexiletine

Contraindications

• Second- or third-degree AV block (unless a cardiac pacemaker is in place).^{1 34 46}

• Cardiogenic shock.^{1 34 46}

Warnings/Precautions

Warnings

Mortality

In CAST study, excessive rate of mortality and nonfatal cardiac arrest reported in patients with asymptomatic, non-life-threatening ventricular arrhythmias and recent MI (>6 days but <2 years previously) who were receiving encainide or flecainide compared with placebo.^{1 2 3 4 5 34}

Limit use of mexiletine in patients with ventricular arrhythmias to those with life-threatening arrhythmias^{1 34} due to mexiletine’s arrhythmogenic potential (see Cardiovascular Effects under Cautions) and the lack of evidence for improved survival for class I antiarrhythmic agents.^{33 34 40 41 42} Use for treatment of less severe arrhythmias currently is not recommended; avoid treatment of asymptomatic VPCs.^{1 34}

Major Toxicities

Cardiovascular Effects

Possible development or exacerbation of arrhythmias; clinical and ECG evaluations are essential prior to and during therapy.^{1 34} Initiate therapy in a hospital.^{1 34}

Use with caution in patients with preexisting first-degree AV block, sinus node dysfunction, or intraventricular conduction disturbances.^{1 34} Continuous monitoring recommended for patients with second- or third-degree AV block and an operative ventricular pacemaker.^{1 34} (See Contraindications under Cautions.)

Possible exacerbation of hypotension and CHF; use with caution in patients with these conditions.^{1 34}

Hepatic Effects

Possible abnormal liver function test results (AST elevations ≥3 times the ULN),^{1 34 44} especially during initial weeks of therapy in patients with CHF or AMI and/or patients who have received blood transfusions or other drug therapies.^{1 34} Discontinuance of therapy usually is not required.^{1 34} Severe hepatic injury, including hepatic necrosis, reported rarely.^{1 34}

Carefully evaluate patients who develop elevated serum concentrations of hepatic enzymes and those with signs or symptoms suggestive of liver dysfunction; consider discontinuance of therapy if enzyme elevations are persistent or increasing.^{1 34}

Hematologic Effects

Possible leukopenia, agranulocytosis, and thrombocytopenia, ^{1 34} especially in severely ill patients receiving concurrent therapy with drugs known to cause adverse hematologic effects (e.g., procainamide, vinblastine).^{1 34}

Carefully evaluate patients in whom substantial hematologic changes occur; consider discontinuing therapy.^{1 34} Blood cell counts generally return to normal within 1 month following discontinuance.^{1 34}

General Precautions

Seizures

Seizures reported rarely; discontinuance of therapy may be necessary.^{1 34} Use with caution in patients with a history of seizure disorder.^{1 34}

Effects on Urinary Excretion

Substantial changes in urinary pH may affect urinary excretion of mexiletine; avoid concomitant drug therapy or dietary regimens that may markedly affect urinary pH.^{1 11 12 21 34}

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk.^{1 21 34} Discontinue nursing or the drug.^{1 34}

Pediatric Use

Safety and efficacy not established.^{1 34 44 47}

Hepatic Impairment

Possible prolonged elimination.^{1 8 9 12 13 34} Careful monitoring recommended (including in those with hepatic impairment secondary to CHF).^{1 8 9 34} Consider dosage reduction.^{1 8 12 34 44}

Common Adverse Effects

Nausea,^{1 14 18 19 20 34} vomiting,^{1 18 19 20 34} heartburn,^{1 14 20 34} dizziness^{1 5 18 19 34} or lightheadedness,^{1 34} tremor,^{1 18 20 34} nervousness,^{1 34} chest pain, ^{1 34} coordination difficulties,^{1 34} headache,^{1 15 34} blurred vision/visual disturbances.^{1 20 34}

Drug Interactions

Metabolized by various CYP isoenzymes,^{1 9} principally by CYP2D and CYP1A2.³⁹

Drugs Affecting Hepatic Microsomal Enzymes

Hepatic enzyme inducers: Potential pharmacokinetic interaction (decreased plasma mexiletine concentrations).^{1 8 9 10 11 12 13 21 25 34}

Hepatic enzyme inhibitors: Potential pharmacokinetic interaction (decreased mexiletine clearance).^{1 49 50}

Drugs Affecting Gastric Emptying

Drugs that delay gastric emptying may reduce rate of mexiletine absorption^{1 34} (since mexiletine is absorbed in the small intestine^{1 11 12 13 21 34} ); conversely, drugs that accelerate gastric emptying may increase rate of mexiletine absorption.^{1 10 11 21 34}

Drugs Affecting Urinary pH

Drugs that markedly alter urinary pH may affect elimination of mexiletine; urinary acidification accelerates elimination; alkalinization slows elimination.¹ Avoid concomitant drug therapy that markedly affects urinary pH.^{1 11 12 21 34}

Specific Drugs

Mexiletine Pharmacokinetics

Absorption

Bioavailability

About 90% absorbed following oral administration, with peak plasma concentrations attained in 2–3 hours.¹ Undergoes low first-pass metabolism.^{1 34}

Onset

Onset of action is usually within 30–120 minutes.^{1 34}

Plasma Concentrations

Plasma mexiletine concentrations of ≥0.5 mcg/mL generally required to suppress ventricular arrhythmias; concentrations >2 mcg/mL associated with adverse CNS effects.¹

Special Populations

Decreased rate of absorption in patients with AMI or other conditions that delay gastric emptying.¹

Distribution

Plasma Protein Binding

50–60%.¹

Elimination

Metabolism

Extensively metabolized in the liver^{1 9 10 34} by various CYP isoenzymes,⁹ including CYP2D and CYP1A2.³⁹ Pharmacologic activity results principally from the parent drug.^{9 10}

Elimination Route

About 8–15% of a dose is excreted in urine as unchanged drug.^{12 13}

Half-life

10–12 hours.¹

Special Populations

In patients with hepatic impairment, possible decreased metabolism^{1 8 12 34 44} and prolonged elimination.^{1 8 9 12 13 34}

Stability

Storage

Oral

Capsules

20–25°C.¹

Actions

• Combines with fast sodium channels within the myocardium and inhibits rapid sodium influx, which decreases the maximal rate of depolarization of phase 0 of the action potential.^{1 8 10 11 12 21 34}

• Inhibits recovery after repolarization in a time- and voltage-dependent manner, which is associated with subsequent dissociation of the drug from the sodium channels.^{35 36 37 39}

• Increases the effective refractory period (ERP) relative to the duration of the action potential (ERP/APD)^{1 8 9 10 12 14 21 34} and reduces ventricular automaticity by raising the threshold for spontaneous firing of ventricular pacemaker cells.¹⁰

• Exhibits electrophysiologic effects characteristic of class IB antiarrhythmic agents,^{8 10 12 35 36 37 38} which rapidly attach to and dissociate from transmembrane sodium channels.^{1 8 9 12 35 36 37}

• Causes little or no prolongation of PR and QT intervals or QRS complex.^{1 8 9 10 12 14 21 34} Has no clinically important effect on heart rate, systemic arterial BP, or myocardial function in healthy individuals or patients with cardiovascular disease.^{1 10 11 12 14 21 34}

Advice to Patients

• Potential for toxicity (e.g., cardiovascular, hepatic).¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 34}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 34}

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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